Biological implication of conformational flexibility in ouabain: observations with two ouabain phosphate isomers

Biochemistry
A KawamuraJ M Hamlyn

Abstract

Ouabain is a highly polar and unusually potent sodium pump inhibitor that possesses uncommon conformational flexibility in its steroid A-ring moiety. The biological significance of ring flection in the cardiotonic steroids has not been described. Accordingly, we prepared ouabain 1,5,19- and 1,11,19-phosphates. The former stabilizes the steroid A-ring chair conformation and the latter locks the A-ring in the half-boat conformation and decreases flection of the ABC-ring moiety. Using a dog kidney cell line (MDCK) in a pH microphysiometer (Cytosensor), ouabain and its 1,5,19-phosphate at 10(-5) M reduced the rate of extracellular acidification by 15-20%. During inhibitor washout, the rate of recovery from the 1,5,19-phosphate analogue was approximately 3 times faster than ouabain. The 1,11,19-phosphate at 10(-4) M elicited a weak ( approximately 7%) response, and the effects reversed approximately 44-fold faster than ouabain. Studies with purified Na(+),K(+)-ATPase showed that ouabain and its 1,5,19-phosphate analogue were of similar efficacy (EC(50) = 1.1 and 5.2 x 10(-7) M, respectively) and >100-fold more potent than the 1,11,19-phosphate analogue. Studies of the binding kinetics showed that the 1,5,19-phosphate analogue bound ...Continue Reading

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Citations

Mar 16, 2011·Clinical and Experimental Pharmacology & Physiology·Masamichi YoshikaHakuo Takahashi
Nov 1, 2001·Proceedings of the National Academy of Sciences of the United States of America·O AizmanA Aperia
Dec 1, 2015·Chemistry : a European Journal·Kengo MasudaMasayuki Inoue
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May 24, 2003·Annals of the New York Academy of Sciences·Oleg Aizman, Anita Aperia
Mar 19, 2009·Chemistry, an Asian Journal·Maddi Sridhar ReddyPierre Deslongchamps
Feb 23, 2012·Chemistry : a European Journal·Brian Heasley
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Sep 1, 2017·Journal of Cellular Biochemistry·Israel José Pereira GarciaHérica de Lima Santos
Jan 17, 2015·Journal of the American Chemical Society·Hans RenataPhil S Baran

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